New lung-on-chip technology with iPS cells reveals distinct immune responses for flu and COVID-19
Scientists have developed groundbreaking airway and alveolus chip models using induced pluripotent stem cells, revealing how SARS-CoV-2 and influenza trigger dramatically different immune responses in upper versus lower respiratory regions. The research offers new insights into COVID-19 pathology and potential therapeutic targets.
Isogenic stem cell chips unlock respiratory virus secrets
Researchers at Kyoto University have achieved a significant breakthrough in understanding respiratory viral infections by creating sophisticated lung-on-chip models that replicate distinct regions of the human respiratory tract. Published in Nature Biomedical Engineering on 16 July 2025, the study reveals striking differences in how SARS-CoV-2 and influenza A virus trigger immune responses in airway versus alveolar tissues.
The innovative approach addresses a critical limitation in viral research: the difficulty of obtaining matched cell types from different respiratory regions of the same patient. By using isogenic induced pluripotent stem (iPS) cells – cells genetically identical but derived from a single source – the team created both airway-on-chip and alveolus-on-chip models that enable direct comparison of host immune responses.
Schematic illustration of the iPSC cell-derived airway and alveolus chips. © Ryuji Yokokawa, et. al. Kyoto University, Nature Biomedical Engineering https://doi.org/10.1038/s41551-025-01444-2
Dysregulated immune responses reveal COVID-19 vulnerabilities
The research uncovered a concerning pattern in SARS-CoV-2 infection. Whilst airway epithelial cells mounted a robust early interferon-dependent immune response – a crucial first line of antiviral defence – alveolar cells showed markedly dysregulated and delayed interferon activation. This disparity may explain why COVID-19 can progress to severe lung damage in the deeper respiratory regions.
“SARS-CoV-2-infected airway chips show a robust early interferon-dependent innate immune response, while alveolus chips show dysregulated and delayed interferon activation alongside a significantly upregulated chemokine pathway,” the authors noted in their findings.
The delayed immune response in alveolar tissue created a vulnerability window where viral replication could proceed unchecked. Significantly, when researchers pretreated infected alveolus chips with interferon-β – a therapeutic agent considered during the COVID-19 pandemic – viral replication was successfully inhibited, demonstrating the model’s potential for drug screening applications.
Influenza triggers more devastating cellular damage
In stark contrast to SARS-CoV-2, influenza infection induced a more pronounced and immediate innate immune response across both chip types, but paradoxically caused greater cellular damage. The research revealed that influenza activated crucial type I interferon genes including IFNL1, IFNL2, IFNB1, and multiple interferon-stimulated genes in both airway and alveolar epithelia.
However, this robust immune activation came at a cost. Influenza infection significantly reduced multiciliated cells in airway epithelium and caused substantial damage to alveolar type 2 (AT2) cells, which are essential for lung function and repair. The findings suggest that whilst a strong early immune response can limit viral spread, it may also contribute to tissue damage and respiratory complications.
Technical innovation enables unprecedented insights
The study’s technical achievements represent a significant advance in respiratory disease modelling. The team successfully differentiated iPS cells into lung progenitor cells, which were then cultured on microfluidic chips to form either multiciliated airway epithelium or surfactant-producing alveolar epithelium. Human umbilical vein endothelial cells were co-cultured to replicate the tissue interface found in human lungs.
RNA sequencing analysis revealed that SARS-CoV-2 infection upregulated 162 genes and downregulated 40 genes in airway epithelium, with strong activation of interferon pathways. In contrast, alveolar epithelium showed upregulation of only 65 genes and downregulation of 98 genes, with limited interferon pathway activation but significant chemokine pathway upregulation.
Implications for therapeutic development
The research provides crucial insights into why different respiratory regions respond variably to viral infections. The authors noted that “a dysregulated and delayed type I interferon activation with upregulated chemokine pathways may lead to uncontrolled viral replication and recruitment of immune cells,” potentially explaining the progression to severe COVID-19 in some patients.
The platform’s ability to test therapeutic interventions was demonstrated through the interferon-β experiments, suggesting significant potential for drug discovery and screening applications. The isogenic nature of the cell source enables researchers to study tissue-specific responses without the confounding variables inherent in comparing cells from different donors.
Future applications
Whilst the current models don’t incorporate mechanical factors such as breathing motions or fluidic flow – important elements that influence immune responses in vivo – the researchers acknowledge these as priorities for future development. The system also uses identical endothelial cell conditions for both chip types, which may not fully capture regional differences in the human respiratory tract.
Despite these limitations, the technology offers unprecedented opportunities for studying respiratory viral pathogenesis and testing interventions across different lung regions using genetically matched cells. As respiratory virus threats continue to emerge, such platforms could prove invaluable for understanding disease mechanisms and developing targeted therapeutics.
The research demonstrates how sophisticated in vitro models can reveal fundamental biological insights that may inform clinical approaches to respiratory viral infections, potentially improving outcomes for patients with severe COVID-19 and other respiratory diseases.
Reference
Yadav, S., Fujimoto, K., Takenaga, T., et. al. (2025). Isogenic induced-pluripotent-stem-cell-derived airway- and alveolus-on-chip models reveal specific innate immune responses. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-025-01444-2
